ClinVar

Description

The p.Arg192Cys variant in TNNI3 has been reported in 1 individual with HCM and 1 child with RCM (Millat 2010, van den Wijngaard 2011). In addition, the p.Arg19 2Cys variant has been identified by our laboratory in 3 children with RCM and 1 child with RCM and HCM, and identified as an apparently de novo occurrence in 3 of these cases. It was absent from large population studies. Computational predi ction tools and conservation analysis suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. Furthermore, three different pathogenic or likely pathogenic variants at th is position, (p.Arg192His, p.Arg192Pro, and p.Arg192Leu) have been identified in multiple individuals with HCM and/or RCM and have occurred de novo in multiple cases, strongly supporting that changes at this position may lead to disease. In summary, this variant meets criteria to be classified as pathogenic for RCM in an autosomal dominant manner based on the presence of this variant in affected i ndividuals with multiple de novo occurrences, absence from controls, and presenc e of other pathogenic variants involving this codon. ACMG/AMP Criteria applied: PM6_Strong, PM2, PS4_Moderate, PM5, PP3.